Oral composition for calculus retardation

ABSTRACT

Oral compositions, such as toothpaste, mouthwash, and the like, containing certain polyphosphonic acids and their salts which retard dental calculus formation without damaging tooth structure.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of the copending applicationof Homer W. McCune and Nathaniel B. Tucker, Ser. No. 693,713, filed Dec.27, 1967, which is a continuation-in-part of copending application Ser.No. 668,702, filed Sept. 18, 1967, which in turn is acontinuation-in-part of copending application Ser. No. 512,548, filedDec. 8, 1965, all now abandoned.

BACKGROUND OF THE INVENTION

The field of this invention is "oral compositions" which term is usedherein to designate products which in the ordinary course of usage areretained in the oral cavity for a time sufficient to contactsubstantially all of the dental surfaces, but are not intentionallyingested. Such products include, for example, dentifrices, mouthwashes,prophylaxis pastes and topical solutions.

Dental calculus, or tartar as it is sometimes called, is a deposit whichforms on the surfaces of the teeth at the gingival margin. Supraginivalcalculus appears principally in the areas near the orifices of thesalivary ducts; e.g., on the lingual surfaces of the lower anteriorteeth and on the buccal surfaces of the upper first and second molars,and on the distal surfaces of the posterior molars.

Mature calculus consists of an inorganic portion which is largelycalcium phosphate arranged in a hydroxylapatite crystal latticestructure similar to bone, enamel and dentine. An organic portion isalso present and consists of desquamated epithelial cells, leukocytes,salivary sediment, food debris and various types of microorganisms.

As the mature calculus develops, it becomes visibly white or yellowishin color unless stained or discolored by some extraneous agency. Inaddition to being unsightly and undesirable from an aestheticstandpoint, the mature calculus deposits are constant sources ofirritation of the gingiva and thereby are a contributing factor togingivitis and other diseases of the supporting structures of the teeth,the irritation decreasing the resistance of tissues to endogeneous andexogenous organisms.

A wide variety of chemical and biological agents have been suggested inthe art to retard calculus formation or to remove calculus after it isformed. Mechanical removal of this material periodically by the dentistis, of course, routine dental office procedure.

The chemical approach to calculus inhibition generally involveschelation of calcium ion which prevents the calculus from forming and/orbreaks down mature calculus by removing calcium. A number of chelatingagents have been employed for this purpose. See, for example, BritishPatent 490,384, granted Feb. 15, 1937, which discloses oral compositionscontaining ethylenediamine-tetraacetic acid, nitrilotriacetic acid andrelated compounds as anticalculus agents; German Auslegeschrift1,149,138, published May 22, 1963, which discloses certain water-solublediglycolates as anticalculus agents; and U.S. Pat. No. 1,516,206 whichdiscloses oral compositions containing various sugar lactones for thispurpose.

Although certain of the art-disclosed chelators are purportedly safe foruse on dental enamel, the chemical similarity of calculus to the toothstructure limits the usefulness of the chelation approach since the moreeffective chelators can seriously damage the tooth structure bydecalcification. Thus, the development of oral compositions whicheffectively retard calculus by calcium chelation has been impeded bysafety considerations.

SUMMARY OF THE INVENTION

It has now been discovered that certain polyphosphonic acids and saltsthereof (referred to collectively hereinafter as "polyphosphonates")possess the surprising capacity to retard the development of dentalcalculus without removing calcium from dental enamel or otherwisedamaging the tooth structure when employed in oral compositionsmaintained within defined pH limits.

Operable polyphosphonates for use in the compositions of this inventionare characterized in that their molecular structure contains at leasttwo geminal or three vicinal phosphono groups. Although these compoundsmay possess only nominal calcium sequestering capacities in the pH rangecharacteristic of oral compositions, they effectively retard calculusformation by a mechanism that is believed to involve the inhibition ofhydroxylapatite crystal growth as will be discussed more fullyhereinafter.

Unlike inorganic polyphosphates such as pyrophosphates, thepolyphosphonates employed in the compositions of this invention resisthydrolysis in aqueous products and therefore remain in an active formthroughout the normal shelf-life of such products.

It is therefore an object of this invention to provide novel oralcompositions which retard the formation of calculus without otherwiseaffecting the tooth structure.

It is another object of this invention to provide an improved method forretarding the development of dental calculus.

Other objects will become apparent from the following detaileddescription.

DETAILED DESCRIPTION OF THE INVENTION

This invention is an oral composition effective in inhibiting theformation of dental calculus without adversely affecting the toothstructure comprising from about .01% to about 10% by weight of apolyphosphonate selected from the group consisting of those of theformulae: ##STR1## wherein R₁ and R₂ are hydrogen or CH₂ OH; n is aninteger of from 3 to 10; R₃ is hydrogen, alkyl containing from 1 toabout 20 carbon atoms, alkenyl containing from 2 to about 20 carbonatoms, aryl (e.g., phenyl and naphthyl), phenylethenyl, benzyl, halogen(e.g., chlorine, bromine, and fluorine), amino, substituted amino (e.g.,dimethylamino, diethylamino, N-hydroxy-N-ethylamino, acetylamino), --CH₂COOH, --CH₂ PO₃ H₂,

--CH(PO₃ H₂) (OH) or --CH₂ CH(PO₃ H₂)₂ ; R₄ is hydrogen, lower alkyl(e.g., methyl, ethyl, propyl, and butyl), amino, benzyl, halogen (e.g.,chlorine, bromine and fluorine), hydroxyl, --CH₂ COOH, --CH₂ PO₃ H₂, or--CH₂ CH₂ PO₃ H₂ ; or a pharmaceutically acceptable salt thereof such asalkali metal (e.g., sodium and potassium), alkaline earth metal (e.g.,calcium and magnesium), and ammonium or low molecular weight substitutedammonium (e.g., mono-, di-, and triethanolammonium) salts, and a carriersuitable for use in the oral cavity, the pH of the composition beingwithin the range from about 5.0 to about 11.0.

Operable polyphosphonates of the above Formula I include

propane-1,2,3-triphosphonic acid;

butane-1,2,3,4-tetraphosphonic acid;

hexane-1,2,3,4,5,6-hexaphosphonic acid;

hexane-1-hydroxy-2,3,4,5,6-pentaphosphonic acid;

hexane-1,6-dihydroxy-2,3,4,5-tetraphosphonic acid;

pentane-1,2,3,4,5-pentaphosphonic acid;

heptane-1,2,3,4,5,6,7-heptaphosphonic acid;

octane-1,2,3,4,5,6,7,8-octaphosphonic acid;

nonane-1,2,3,4,5,6,7,8,9-nonaphosphonic acid;

decane-1,2,3,4,5,6,7,8,9,10-decaphosphonic acid;

and the pharmaceutically acceptable salts of these acids, e.g., sodium,potassium, calcium, magnesium, ammonium, triethanolammonium,diethanolammonium, and monoethanolammonium salts.

Among the operable polyphosphonates encompassed by the above Formula IIare

ethane-1-hydroxy-1,1-diphosphonic acid;

methanediphosphonic acid;

methanehydroxydiphosphonic acid;

ethane-1,1,2-triphosphonic acid;

propane-1,1,3,3-tetraphosphonic acid;

ethane-2-phenyl-1,1-diphosphonic acid;

ethane-2-naphthyl-1,1-diphosphonic acid;

methanephenyldiphosphonic acid;

ethane-1-amino-1,1-diphosphonic acid;

methanedichlorodiphosphonic acid;

nonane-5,5-diphosphonic acid;

n-pentane-1,1-diphosphonic acid;

methanedifluorodiphosphonic acid;

methanedibromodiphosphonic acid;

propane-2,2-diphosphonic acid;

ethane-2-carboxy-1,

1-diphosphonic acid;

propane-1-hydroxy-1,1,3-triphosphonic acid;

ethane-2-hydroxy-1,1,2-triphosphonic acid;

ethane-1-hydroxy-1,1,2-triphosphonic acid;

propane-1,3-diphenyl-2,2-diphosphonic acid;

nonane-1,1-diphosphonic acid;

hexadecane-1,1-diphosphonic acid;

pent-4-ene-1-hydroxy-1,1-diphosphonic acid;

octadec-9-ene-1-hydroxy-1,1-diphosphonic acid;

3-phenyl-1,1-diphosphonoprop-2-ene;

octane-1,1-diphosphonic acid;

dodecane-1,1-disphosphonic acid;

phenylaminomethanediphosphonic acid;

naphthylaminomethanediphosphonic acid;

N,n-dimethylaminomethanediphosphonic acid;

N-(2-hydroxyethyl)-aminomethanediphosphonic acid;

N-acetylaminomethanediphosphonic acid;

aminomethanediphosphonic acid;

and the pharmaceutically acceptable salts of these acids, e.g., sodium,potassium, calcium, magnesium ammonium, triethanolammonium,diethanolammonium and monoethanolammonium salts.

Mixtures of any of the foregoing phosphonic acids and/or salts can beused in the compositions of this invention.

Ethane-1-hydroxy-1,1-diphosphonic acid, an especially preferredpolyphosphonate, has the molecular formula CH₃ C(OH)(PO₃ H₂)₂.(According to nomenclature by radicals, the acid might also be named1-hydroxyethylidene diphosphonic acid.) The most readily crystallizablesalt of this acid is obtained when three of the acid hydrogens arereplaced by sodium. Preferred salts for the purpose of this inventionare the trisodium hydrogen salt which has the structure: ##STR2## andthe disodium salt.

The trisodium hydrogen salt normally crystallizes as the hexahydratewhich loses some water during air-drying to yield a mixture of the hexa-and monohydrate averaging 3 to 4 molecules of water of hydration.

While any pharmaceutically acceptable salt ofethane-1-hydroxy-1,1-diphosphonic acid can be used in the practice ofthis invention, the tetrasodium salt, the trisodium hydrogen salt, thedisodium dihydrogen salt, the monosodium trihydrogen salt, themonocalcium salt and the mixtures thereof preferred. The otherpharmaceutically acceptable salts and mixtures thereof are alsosuitable. These compounds can be prepared by any suitable method,however, an especially preferred method is disclosed in copendingapplication Ser. No. 553,648, fled May 31, 1966, by Oscar T. Quimby etal., now Patent No. 3,400,149.

Methanehydroxydiphosphonic acid and related compounds operable hereincan be prepared, for example, by reaction of phosgene with an alkalimetal dialkyl phosphite. A complete description of these compounds andthe method for preparing same is found in copending patent applicationSer. No. 517,073, filed Dec. 29, 1965, by Oscar T. Quimby, now PatentNo. 3,422,137.

Methanediphosphonic acid and related compounds useful herein aredescribed in detail in U.s. Patent 3,213,030, granted Oct. 19, 1965. Apreferred method of preparing such compounds is disclosed in copendingapplication Ser. No. 218,862, filed Aug. 23, 1962, by Clarence H. Roy,now Patent No. 3,251,907.

Ethane-1,1,2-triphosphonic acid and related compounds which can be usedin the compositions of this invention as well as a method for theirpreparation are fully described in copending patent application Ser. No.602,161, filed Dec. 16, 1966, by Oscar T. Quimby.

Propane-1,1,3,3-tetraphosphonic acid and related compounds usefulherein, and a method for preparing same are fully disclosed in copendingapplication Ser. No. 507,662, filed Nov. 15, 1965, by Oscar T. Quimby,now Patent No. 3,400,176.

Pentane-2,2-diphosphonic acid and related compounds can be prepared inaccordance with the method described by G. M. Kosolopoff in J. Amer.Chem. Soc., 75, 1500 (1953).

Propane-1,2,3-triphosphonic acid and salts thereof can be prepared by aprocess disclosed in the commonly assigned copending application of D.Allan Nicholson and Darrel Campbell, Ser. No. 694,002, filed Dec. 27,1967.

Butane-1,2,3,4-tetraphosphonic acid and salts thereof can be prepared bya process disclosed in the commonly assigned copending application of D.Allan Nicholson and Darrel Campbell, Ser. No. 694,003, filed Dec. 27,1967.

The higher aliphatic vicinal polyphosphonates and salts thereof can beprepared by the process disclosed in the commonly assigned copendingapplication of D. Allan Nicholson and Darrel Campbell, Ser. No. 693,898,filed Dec. 27, 1967.

The concentration of polyphosphonate in the oral compositions of thisinvention can range from about .01% to about 10% by weight. Oralcompositions which in the ordinary course of usage could be accidentallyingested should contain lower concentrations of polyphosphonate. Thus, amouthwash in accordance with this invention preferably contains lessthan about 3% by weight of polyphosphonate. Dentifrice compositions,topical solutions and prophylaxis pastes, the latter to be administeredprofessionally, can contain up to about 10% by weight, preferably fromabout 0.1% to about 5.0% by weight of polyphosphonate.

The pH of the composition of this invention can range from about 5.0 toabout 11. Below about pH 5.0 damage to the dental enamel can occur inspite of the relative safety of the polyphosphonates. Above about pH11.0 difficulty is encountered in formulating products havingsatisfactory flavor and mildness. A preferred pH range is from about 7.0to about 10. The pH of the composition, of course, is determinative ofthe predominant salt form of the polyphosphonates present therein. Forexample, at pH 7.0 ethane-1-hydroxy-1,1 -diphosphonate is predominantlyin the disodium form.

While it is not intended that this invention be limited by a particulartheory of operation, it has been observed that the polyphosphonatesencompassed herein interfere with the progress of calculus formation byinterferring with the conversion of amorphous calcium phosphate tocrystalline calcium hydroxylapatite. Amounts of polyphosphonates whichare much too small to chelate any appreciable quantities of calcium havebeen found to retard the formation of calcium hydroxylapatite. Thisselective action on the formative calculus deposits withoutdemineralizing action on the dental enamel is surprising.

The efficacy of the compositions of this invention in calculusprophylaxis was demonstrated by the Rat Calculus and Crystal GrowthInhibition Tests which were conducted as follows:

Rat calculus study (topical)

Two groups of 20- to 21-day-old Holtzman-Sprague-Dawley strain rats,each group comprising one male and one female member of each of 10liters, were employed in this test, one group serving as the control andthe other serving as the test group. Both groups of animals were placedon a calculus inducing diet consisting of 63% cornstarch, 32% non-fatdry milk, 2% liver powder and 3% celluflour. Topical applications of a0.5% aqueous solution of trisodium hydrogenethane-1-hydroxy-1,1-diphosphonate adjusted to pH 10.0 were made on theteeth of each of the animals in the test group for about one minutetwice daily, five days per week for three weeks. Similar applications ofwater were made to each animal in the control group during theexperimental period.

Three weeks after the commencement of the test, the animals weresacrificed and their molars were graded for severity of calculus byassessing the area and depth of accumulation on each of the 44 dentalsurfaces examined in each animal. Grading was made on a 0-3 scale foreach surface, 0 being no detectable calcified deposits, 3 being coverageof 50-100% of the surface with a thick deposit and intermediate valuesrepresenting gradations between these extremes. The total calculus scorefor each animal was determined by adding the grades for each of the 44surfaces.

The results obtained in two such experiments are set forth in Table 1below.

                  TABLE I                                                         ______________________________________                                                   Average of Total Calculus Scores                                                                     Percent                                     Experiment No.                                                                             Test      Control    reduction                                   ______________________________________                                        1             2.4       6.8       65                                          2            11.2      27.2       59                                          ______________________________________                                    

It can be seen that substantial reductions in calculus formation areattained with topically applied compositions in accordance with thisinvention.

Crystal growth inhibition determination

As hereinbefore stated, the polyphosphonates inhibit the growth ofcalcium hydroxylapatite crystals and in this way interfere with thenormal formation of calcium hydroxylapatite from solution. This test isto determine the effect of the polyphosphonates on the calcium phosphateformed on addition of calcium ion to orthophosphate ion at constant pH.The procedure is as follows:

1 ml. of a 0.1 M stock solution of NaH₂ PO₄.sup.. H₂ O is diluted with22 ml. of distilled water. 1 ml. of an aqueous solution of thepolyphosphonate to be tested (at a concentration sufficient to providethe desired ultimate concentration in the reaction mixture) is added tothe diluted NaH₂ PO₄ solution and the solution is adjusted to pH 7.4with sodium hydroxide. To this solution is added 1 ml. of a 0.1 Msolution of CaCl₂.sup.. 2H₂ O preadjusted to pH 7.4 with sodiumhydroxide. This mixture is held at a constant pH 7.4 throughout thereaction period.

After a sufficient reaction time as determined by the operator,generally within 90 minutes, the solution is filtered through a 0.45μMillipore filter pad. The precipitate is air-dried and analyzed by X-raydiffraction. The solid calcium phosphate precipitated from theabove-described solution without a polyphosphonate gives a typicalhydroxylapatite pattern, while the calcium phosphate precipitated underthe same conditions but in the presence of small amounts of thepolyphosphonates of this invention is amorphous to X-rays.

Those compounds which were effective in inhibiting the growth ofhydroxylapatite crystals at concentrations of less than 1.5 × 10.sup.⁻³m. under the conditions of this test were found to be effective inreducing calculus formation in rats, while several compounds outside thescope of this invention that had little or no effect in this test didnot reduce calculus in rats.

Table 3 below shows the concentration of various polyphosphonates testedrequired to inhibit the formation of calcium hydroxylapatite under theconditions specified above.

                                      TABLE 3                                     __________________________________________________________________________                                M Concentration                                   Compound                    for Inhibition                                    __________________________________________________________________________    Ethane-1-hydroxy-1,1-diphosphonic acid, trisodium                              salt                       2.00×10.sup.-.sup.4                         Methane diphosphonic acid, trisodium salt                                                                 1.82×10.sup.-4                              Methanehydroxydiphosphonic acid, disodium salt                                                            2.04×10.sup.-.sup.4                         Ethane-1,1,2-triphosphonic acid, tetrasodium salt                                                         2.00×10.sup.-.sup.4                         Propane-1,1,3,3-tetraphosphonic acid, hexasodium                               salt                       1.16×10.sup.-.sup.3                         Ethane-1-amino-1,1-diphosphonic acid                                                                      1.00×10.sup.-.sup.4                         Methanedichlorodiphosphonic acid. trisodium salt                                                          2.00×10.sup.-4                              Nonane-5,5-diphosphonic acid                                                                              2.00×10.sup.-.sup.4                         n-Pentane-1,1-diphosphonic acid                                                                           2.00×10.sup.-4                              Nonane-1,1-diphosphonic acid, disodium salt                                                               2.01×10.sup.-.sup.4                         Methanedibromodiphosphonic acid                                                                           5.04×10.sup.-.sup.5                         Ethane-2-carboxy-1,1-diphosphonic acid, tetrasodium                            salt                       2.26×°.sup.-.sup.4                   Propane-1-hydroxy-1,1,3-triphosphonic acid, penta-                             sodium salt                1.02×10.sup.-.sup.4                         Ethane-1-hydroxy-1,1,2-triphosphonic acid, penta-                              sodium salt                1.13×10.sup.-.sup.3                         Ethane-2-hydroxy-1,1,2-triphosphonic acid, penta-                              sodium salt                1.05×10.sup.-.sup.3                         Methaneaminodiphosphonic acid                                                                             2.00×10.sup.-4                              Phenylaminomethanediphosphonic acid                                                                       2.60×10.sup.-.sup.4                         N,N-dimethylaminomethanediphosphonic acid                                                                 5.00×10.sup.-.sup.5                         N-(2-hydroxyethyl)aminomethanediphosphonic acid                                                           5.20×10.sup.-5                              N-acetylaminomethanediphosphonic acid                                                                     2.22×10.sup.-.sup.5                         Propane-1,2,3-triphosphonic acid                                                                          2.32×10.sup.-.sup.4                         Butane-1,2,3,4-tetraphosphonic acid                                                                       2.04×10.sup.-.sup.4                         Hexane-1,2,3,4,5,6-hexaphosphonic acid                                                                    2.22×10.sup.-4                              3-phenyl-1,1-diphosphonoprop-2-ene, disodium salt                                                         2.04×10.sup.-.sup.4                         __________________________________________________________________________

The presence of the specified amounts of the polyphosphonates of Table 3in the test solutions of the Crystal Growth Inhibition Test results inthe precipitation of an amorphous calcium phosphate rather thancrystalline calcium hydroxylapatite as occurs without polyphosponate andthe total formation of calcium orthophosphate is greatly decreased. Byway of comparison, ethylenediaminetetraacetic acid and nitrilotriaceticacid which have been suggested for use as anticalculus agents in the artfail to inhibit crystal growth at molar concentrations of 2.45 ×10.sup.⁻³ and 2.54 × 10.sup.⁻³, respectively. At higher concentrations,these prior art compounds prevent precipitation of calcium phosphate inthis test because of their powerful calcium sequestering properties.

The safety of polyphosphonates for use in contact with dental surfacesis determined by the Continuous Immersion Test conducted as follows:Mature human teeth are immersed in aqueous solutions or dispersions oforal compositions containing polyphosphonate in accordance with thisinvention at pH 7.0 and pH 10. Every four hours the teeth are examinedfor decalcification. Under visible light, enamel decalcification can bedetected by a loss of luster, white opaque spots or slight surfaceroughening. The teeth are examined macroscopically and microscopicallyat the end of seven days. If no decalcification is observed through thisperiod, the compositions cause no damage to dental enamel, and areconsidered safe in this respect for use in the oral cavity.

The safety of polyphosphonates for use in contact with dental enamel canalso be established by measuring the amount of phosphate released from agiven area of dental enamel in the course of a standard exposure to anaqueous soluton of the polyphosphonate as fully described by Tucker etal. in U.S. Pat. No. 3,175,951, granted Mar. 30, 1965.

A dentifrice, especially toothpaste, containing a polyphosphonate is apreferred embodiment of this invention. Toothpaste compositionsconventionally contain abrasive materials, sudsing agents, binders,humectants, flavoring and sweetening agents.

The abrasive materials and other adjuncts used in the practice of thisinvention are preferably not sources of much soluble calcium so that thecrystal growth inhibiting capacity of polyphosphonate is not depleted toan extent that its anticalculus activity is impaired. Thus, conventionalabrasives such as dicalcium orthophosphate and calcium carbonate arepreferably not used. However, predominantly β-phase calciumpyrophosphate prepared in accordance with the teachings of Schweizer,U.s. Pat. No. 3,112,247, granted Nov. 26, 1963, which containsrelatively little soluble calcium can be used. An especially preferredclass of abrasives for use herein are the particulate thermosettingpolymerized resins as described by Cooley et al. in U.S. Pat. No.3,070,510, granted Dec. 25, 1962. Suitable resins include, for example,melamines, phenolics, ureas, melamine-ureas, melamine-formaldehydes,urea-formaldehydes, melamine-urea-formaldehydes, cross-linked epoxides,and cross-linked polyesters.

Other suitable abrasives include alumina and the in soluble non-calciummetaphosphates such as sodium metaphosphate. Mixtures of abrasives canalso be used. In any case, the total amount of abrasive in thedentifrice embodiments of this invention can range from 0.5% to 95% byweight of the dentifrice. Preferably, toothpastes contain from 20% to60% by weight of abrasive. Abrasive particle size preferably ranges from2μ to 20μ.

Suitable sudsing agents are those which are reasonably stable and formsuds throughout a wide pH range, preferably non-soap anionic organicsynthetic detergents. Examples of such agents are water-soluble salts ofalkyl sulfate having from 10 to 18 carbon atoms in the alkyl radical,such as sodium lauryl sulfate; water-soluble salts of sulfonatedmonoglycerides of fatty acids having from 10 to 18 carbon atoms, such assodium monoglyceride sulfonates; salts of C₁₀ -C₁₈ fatty acid amides oftaurine, such as sodium N-methyl-N-palmitoyl taurine; salts of C₁₀ -C₁₈fatty acid esters of isethionic acid; and substantially saturatedaliphatic acyl amides of saturated monoaminocarboxylic acids having 2 to6 carbon atoms and in which the acyl radical contains 12 to 16 carbonatoms, such as sodium N-lauroyl sarcoside. Mixtures of two or moresudsing agents can be used.

The sudsing agent can be present in the dentifrice compositions of thisinvention in an amount from 0.5% to 5% by weight of the totalcompositions.

In preparing toothpastes, it is necessary to add some thickeningmaterial to provide a desirable consistency. Preferred thickening agentsare hydroxyethyl cellulose and water-soluble salts of cellulose etherssuch as sodium carboxymethyl cellulose and sodium carboxymethylhydroxyethyl cellulose. Natural gums such as gum karaya, gum arabic, andgum tragacanth can also be used. Colloidal magnesium aluminum silicateor finely divided silica can be used as part of the thickening agent tofurther improve texture. Thickening agents in an amount from 0.5% to5.0% by weight of the total composition can be used.

It is also desirable to include some humectant material in a toothpasteto keep it from hardening. Suitable humectants include glycerine,sorbitol, and other edible polyhydric alcohols. The humectant cancomprise up to about 36% by weight of the toothpaste composition.

Suitable flavoring agents include oil of wintergreen, oil of peppermint,oil of spearmint, oil of sassafras, and oil of clove. Sweetening agentswhich can be used include saccharin, dextrose, levulose and sodiumcyclamate.

Several representative oral compositions illustrating this invention areset forth in the following examples.

Example I

A toothpaste of the following compositions was prepared by conventionalmethods:

    ______________________________________                                                               Parts by weight                                        ______________________________________                                        Water                    31.58                                                Sorbitol                 6.25                                                 Saccharin                0.12                                                 Calcium pyrophosphate.sup.1                                                                            39.00                                                Glycerine                18.00                                                Sodium alkyl (coconut) sulfate                                                                         0.40                                                 Sodium coconut monoglyceride sulfonate                                                                 0.75-Sodium carboxymethyl cellulose 1.15             Magnesium aluminum silicates                                                                           0.40                                                 Flavoring                0.85                                                 Disodium salt of ethane - 1 - hydroxy - 1,1 - diphos-                          phonic acid             1.50                                                 pH 5.90.                                                                      ______________________________________                                         .sup.1 Prepared in accordance with U.S. Patent 3,112,247 granted Nov.         26,1963.                                                                 

This composition effectively retards calculus formation on dental enameland when tested in the Continuous Immersion Test described herein nodecalcification was noted after seven days exposure.

Toothpaste compositions substantially identical to the composition ofExample I are prepared with the trisodium salt of methanediphosphonicacid; the disodium salt of methane-hydroxydiphosphonic acid; ethane-1-amino-1,1 -diphosphonic acid; trisodium salt ofmethanedichlorodiphosphonic acid; and propane-2,2 -diphosphonic acid,respectively, rather than the disodium salt of ethane-1-hydroxy-1,1-diphosphonic acid, adjusting the pH to 5.9. These compositionssubstantially retard calculus formation and do not decalcify dentalenamel.

Example II

A toothpaste was prepared which was substantially identical incomposition to the toothpaste of Example I except that 3.0 parts ratherthan 1.5 parts of disodium dihydrogen ethane-1-hydroxy-1,1-disphosphonate and 30.08 parts rather than 31.58 parts of water wasused. This composition was also found to be effective and caused nodamage to dental enamel after seven days exposure.

The disodium dihydrogen salt of ethane-1-hydroxy-1,1 -diphosphonic acidin the above composition can be replaced by ethane-1-hydroxy-1,1-diphosphonic acid, or any of the potassium, ammonium, or substitutedammonium salts thereof, adjusting the pH of the composition to 7.0, andsubstantially equivalent results are attained.

Example III

Yet another toothpaste was prepared having the following composition:

    ______________________________________                                                               Parts by weight                                        ______________________________________                                        Water                    39.58                                                Sorbitol                 6.25                                                 Saccharin                .12                                                  Abrasive (precipitated urea/formaldehyde                                       condensate)             31.00                                                Glycerine                18.00                                                Sodium alkyl (coconut) sulfate                                                                         .40                                                  Sodium coconut monoglyceride sulfonate                                                                 .75                                                  Sodium carboxymethyl cellulose                                                                         1.15                                                 Magnesium aluminum silicate                                                                            .40                                                  Flavoring                .95                                                  Disodium salt of ethane - 1 - hydroxy-1,1-diphos-                              phonic acid             1.50                                                 pH 5.3.                                                                       ______________________________________                                    

When employed in the customary manner, this toothpaste retards theformation of dental calculus and no decalcification of dental enamel wasobserved after seven days' exposure.

Several additional toothpastes are prepared having essentially the samecomposition as the toothpaste of Example III, but using the tetrasodiumsalt of ethane-1,1,2-triphosphonic acid; the pentasodium salt ofpropane-1-hydroxy-1,1,3-triphosphonic acid; the pentasodium salt ofethane-1-hydroxy-1,1,2-triphosphonic acid; the pentasodium salt ofethane-2-hydroxy-1,1,2-triphosphonic acid;ethane-2-naphthyl-1,1-diphosphonic acid; propane-1,2,3-triphosphonicacid, butane-1,2,3,4-tetraphosphonic acid, andhexane-1,2,3,4,5,6-hexaphosphonic acid, respectively, rather than thedisodium salt of ethane-1-hydroxy-1,1-diphosphonic acid. The pH of thesecompositions is adjusted to 7.0. These toothpaste formulationseffectively retard calculus formation on dental enamel withoutdecalcifying same.

Example IV

A toothpaste composition prepared with 3.0 parts of disodium dihydrogenethane-1-hydroxy-1,1-diphosphonate and 38.08 parts water, but otherwisesubstantially identical to the composition of Example III, was prepared.This composition was found to be effective against calculus formationand caused no observable decalcification of dental enamel after sevendays' exposure.

The disodium dihydrogen salt of ethane-1-hydroxy-1,1-diphosphonic acidemployed in this example can be replaced with dipotassium dihydrogenethane-1-hydroxy-1,1-diphosphonate; diammonium dihydrogenethane-1-hydroxy-1,1-diphosphonate; or bis(triethanolammonium)dihydrogenethane-1-hydroxy-1,1-diphosphonate, respectively, adjusting the pH ofthe composition to 8.0. Substantially equivalent results are obtainedwith these compositions.

Several mouthwash compositions were prepared in accordance with thisinvention as follows:

    __________________________________________________________________________    Example         V     VI    VII   VII                                         __________________________________________________________________________    Component, parts by weight:                                                   Glycerine       10.0  10.0  10.0  10.0                                        Ethyl alcohol   16.5  16.5  16.5  16.5                                        Water           67.172                                                                              67.172                                                                              67.172                                                                              70.192                                      Tween 80.sup.1  .12   .12   .12   .12                                         Saccharin       .045  .045  .045  .02                                         Sodium cyclamate                                                                              .075  0.75  0.75  .04                                         Flavor          .088  .088  .088  .088                                        EHDP.sup.3      3.0   3.0   3.0   1.0                                         pH.sup.3        7.0   8.3  10.0   10.0                                        __________________________________________________________________________     .sup.1 Polyoxyethylene 120-moles of ethylene oxide sorbitan monooleate-a      nomqnic emulsifier supplied by Atlas Powder Company                           .sup.2 Disodium salt of ethane-1-hydroxy-1,1-diphosphonic acid.               .sup.3 Adjusted to value indicated with sodium hydroxide.                

When used in the same manner as conventional mouthwash, at least oncedaily, each of the above compositions materially reduces accumulation ofcalculus on the surfaces of teeth. No decalcification was observed afterseven days exposure of dental enamel to these compositions.

Mouthwash compositions corresponding to Example VII are prepared,substituting the dimagnesium salt of propane-1,1,3,3-tetraphosphonicacid; the disodium salt of propane-2,2-diphosphonic acid; thetetraammonium salt of ethane-2-carboxy-1,1-diphosphonic acid;nonane-5,5-diphosphonic acid; n-pentane-1,1-diphosphonic acid andethane-2-phenyl-1,1-diphosphonic acid, respectively, for the disodiumsalt of ethane-1-hydroxy-1,1-diphosphonic acid and adjusting the pH to10.0. These mouthwash compositions retard calculus formation withoutdamaging tooth structure.

Mouthwash compositions corresponding to Example V are prepared,replacing the disodium salt of ethane-1-hydroxy-1,1-diphosphonic acidwith pent-4-ene-1-hydroxy-1,1-diphosphonic acid;octadec-9-ene-1-hydroxy-1,1-diphosphonic acid;methane-dichlorodiphosphonic acid; methanedibromodiphosphonic acid;phenylaminoethanediphosphonic, respectively. Each of the resultingmouthwash compositions retard calculus formation without damaging dentalenamel.

A number of additional mouthwash compositions are prepared which aresimilar in formulation to the composition of Example VIII but replacingthe disodium salt of ethane-1-hydroxy-1,1-diphosphonic acid with thedisodium salt of hexane-1-hydroxy-2,3,4,5,6-pentaphosphonic acid, thetriammonium salt of hexane-1,6-dihydroxy-2,3,4,5-tetraphosphonic acid,the dicalcium salt of pentane-1,2,3,4,5-pentaphosphonic acid,heptane-1,2,3,4,5,6,7-heptaphosphonic acid andoctane-1,2,3,4,5,6,7,8-octaphosphonic acid, respectively. Thesecompositions are effective in retarding dental calculus formationwithout damaging dental enamel.

Example IX

A prophylaxis paste for use by the dentist for removal of stains andpolishing the teeth after mechanical removal of calculus deposits isformulated as follows:

    ______________________________________                                                              Parts by weight                                         ______________________________________                                        Navajo pumice           77.10                                                 TiO.sub.2               4.00                                                  Glycerine               17.75                                                 Hydroxyethylcellulose   .22                                                   Saccharin               .33                                                   Trisodium salt of ethane-1-hydroxy-1,1-diphos-                                 phonic acid            8.0                                                   pH 8.0                                                                        ______________________________________                                    

When applied to the teeth with a prophylactic rubber cup in theconventional manner, this composition retards the development of newcalculus deposits.

The prophylaxis paste set forth above is modified by replacing thetrisodium salt of ethane-1-hydroxydiphosphonic acid withN,N-dimethylaminoethanediphosphonic acid;N-(2-hydroxyethyl)aminomethanediphosphonic acid;N-acetylaminomethanediphosphonic acid; and aminomethanediphosphonicacid, respectively, with comparable results.

Moreover, dodecane-1,1-diphosphonic acid, the dipotassium salt of3-phenyl-1,1-diphosphonoprop-2-ene, or the dimagnesium salt ofdecane-1,2,3,4,5,6,7,8,9,10-decaphosphonic acid can be used in place ofthe trisodium salt of ethane-1-hydroxy-1,1-diphosphonic acid in thecomposition of Example IX with good results.

Toothpowders and the like can be prepared by conventional methods andcontaining, in addition to the usual ingredients, an amount ofpolyphosphonate within the ranges specified herein, to provide aneffective means of retarding calculus formation without damaging thetooth structure.

Those components other than polyphosphonates which were included in theforegoing examples and various mixtures of those components areillustrative of carriers suitable for use in the oral cavity.

In the reference to pH adjustments in the foregoing examples, it is tobe understood that a base of a cation corresponding to the salt form ofthe polyphosphonate employed is used to adjust to higher pH values. Ineach case in which the polyphosphonate was added in its acid form to theexample compositions, the pH was adjusted to the specified higher valuewith NaOH. Adjustments in pH to more acid levels is accomplished withHCl acid. It will be obvious to those skilled in the art that pHadjustments can be made with any acid or base suitable for use in theoral cavity.

What is claimed is:
 1. .[.An oral.]. .Iadd.A dentifrice.Iaddend.composition effective in inhibiting the formation of dentalcalculus without adversely affecting tooth structure, comprising (1)from about .01% to about 10% by weight of a polyphosphonate selectedfrom the group consisting of those of the formulae: ##STR3##wherein R₁and R₂ are each hydrogen or CH₂ OH; n is an integer of from 3 to 10; R₃is hydrogen, alkyl containing from 1 to about 20 carbon atoms, alkenylcontaining from 2 to about 20 carbon atoms, phenyl, naphthyl,phenylethyl, benzyl, halogen, amino, dimethylamino, diethylamino,N-hydroxy-N-ethylamino, acetylamino, --CH₂ COOH --CH₂ PO₃ H₂, --CH(PO₃H₂)(OH) or --CH₂ CH(PO₃ H₂)₂ R₄ is hydrogen, lower alkyl, amino, benzyl,halogen, hydroxyl --CH₂ COOH, CH₂ PO₃ H₂, or --CH₂ CH₂ PO₃ H₂ ; orapharmaceutically acceptable salt thereof, and (2) .[.a carrier suitablefor use in the oral cavity,.]. .Iadd.from about 0.5% to 95% by weight ofan abrasive material, .Iaddend.the pH of the compositon being within therange from about 5.0 to 11.0, .Iadd.said composition being free ofcalcium abrasives which would yield enough soluble calcium tosignificantly impair the anticalculus activity of said polyphosphonate..Iaddend.
 2. The composition of claim 1 in which the polyphosphonate isethane-1-hydroxy-1,1-diphosphonic acid or a pharmaceutically acceptablesalt thereof.
 3. The composition of claim 1 in which the polyphosphonateis methanediphosphonic acid or a pharmaceutically acceptable saltthereof.
 4. The composition of claim 1 in which the polyphosphonate ismethanedichlorodiphosphonic acid or a pharmaceutically acceptable saltthereof.
 5. The composition of claim 1 in which the polyphosphonate isethane-1-hydroxy-1,1,2-triphosphonic acid or a pharmaceuticallyacceptable salt thereof.
 6. The composition of claim 1 in which thepolyphosphonate is methanehydroxydiphosphonic acid or apharamaceutically acceptable salt thereof.
 7. The composition of claim 1in which the polyphosphonate is propane-1,1,3,3-tetraphosphonic acid ora pharmaceutically acceptable salt thereof.
 8. The composition of claim1 in which the polyphosphonate is ethane-2-carboxy-1,1-diphosphonic acidor a pharmaceutically acceptable salt thereof.
 9. The composition ofclaim 1 in which the polyphosphonate is ethane-1,1,2-triphosphonic acidor a pharmaceutically acceptable salt thereof.
 10. The composition ofclaim 1 in which the polyphosphonate is ethane-1-amino-1,1-diphosphonicacid or a pharmaceutically acceptable salt thereof.
 11. The compositionof claim 1 in which the polyphosphonate is ethanedichlorodiphosphonicacid or a pharmaceutically acceptable salt thereof.
 12. The compositionof claim 1 in which the polyphosphonate is nonane-5,5-diphosphonic acidor a pharmaceutically acceptable salt thereof.
 13. The composition ofclaim 1 in which the polyphosphonate is n-pentane-1,1-diphosphonic acidor a pharmaceutically acceptable salt thereof.
 14. The composition ofclaim 1 in which the polyphosphonate is methanedibromodiphosphonic acidor a pharmaceutically acceptable salt thereof.
 15. The composition ofclaim 1 in which the polyphosphonate ispropane-1-hydroxy-1,1,3-triphosphonic acid or a pharmaceuticallyacceptable salt thereof.
 16. The composition of claim 1 in which thepolyphosphonate is propane-1,2,3-triphosphonic acid or apharmaceutically acceptable salt thereof.
 17. The composition of claim 1in which the polyphosphonate is butane-1,2,3,4-tetraphosphonic acid or apharmaceutically acceptable salt thereof.
 18. The composition of claim 1in which the polyphosphonate is hexane-1,2,3,4,5,6-hexaphosphonic acidor a pharmaceutically acceptable salt thereof.
 19. A toothpastecomposition comprising (1) from about 0.1% to about 5.0% by weight of apolyphosphonate selected from the group consisting of those of theformulae: ##STR4##wherein R₁ and R₂ are each hydrogen or CH₂ OH; n is aninteger of from 3 to 10; R₃ is hydrogen, alkyl containing from 1 toabout 20 carbon atoms, alkenyl containing from 2 to about 20 carbonatoms, phenyl, naphthyl, phenylethenyl, benzyl, halogen, amino,dimethylamino, diethylamino, N-hydroxy-N-ethylamino, acetylamino, --CH₂COOH --CH₂ PO₃ H₂, --CH(PO₃ H₂)(OH) or --CH₂ CH(PO₃ H₂)₂ R₄ is hydrogen,lower alkyl, amino, benzyl, halogen, hydroxyl, --CH₂ COOH, --CH₂ PO₃ H₂,or --CH₂ CH₂ PO₃ H₂ ; or a pharmaceutically acceptable salt thereof, and(2) from about 20% to about 60% by weight of an abrasive material, thepH of said composition being within the range from about 7 to about 10,.Iadd.said composition being free of calcium abrasives which would yieldenough soluble calcium to significantly impair the anticalculus activityof said polyphosphonate. .Iaddend.
 20. The composition of claim 19 inwhich the polyphosphonate is ethane-1-hydroxy-1,1-diphosphonic acid or apharmaceutically acceptable salt thereof. .Iadd.21. The composition ofclaim 19 wherein the abrasive material is selected from the groupconsisting of β-phase calcium pyrophosphate, thermosetting polymerizedresins, alumina and insoluble non-calcium metaphosphates. .Iaddend.